The invention generally relates to the formation and application of barrier materials in a tissue region, e.g., to close vascular puncture sites in humans and other animals.
There are over seven million diagnostic and therapeutic coronary interventions performed each year. By far, the majority of these interventions are performed using percutaneous puncture of the femoral artery to gain access to the arterial system.
Once the intervention is concluded, the vascular puncture site has to be sealed to prevent bleeding, while natural healing processes close the puncture site. Conventional management of the puncture site has typically involved external compression using, e.g., digital pressure, C-clamps, or sandbags, followed by immobilization and bedrest. Proper placement of compression devices to stop bleeding calls for trained clinical skills. Likewise, strong nursing skills are required to monitor for rebleeding. The patient can suffer local discomfort, which may exceed the pain associated with the diagnostic or therapeutic procedure requiring vascular access in the first instance. Complications are not uncommon, which can lead to prolonged hospitalization, transfusion, and direct surgical repair of the puncture site.
Various alternative methods for sealing a vascular puncture site have been tried. For example, collagen plugs have been used to occlude the puncture orifice. The collagen plugs are intended to activate platelets and accelerate the natural healing process. Holding the collagen seals in place using an anchor located inside the artery has also been tried. Still, patient immobilization is required until clot formation stabilizes the site. Other problems, such as distal embolization of the collagen, rebleeding, and the need for external pressure to achieve hemostatis, also persist.
As another example, devices that surgically suture the puncture site percutaneously have also been used. The devices require the practice of fine surgical skills to place four needles at a precise distance from the edges of the puncture orifice and to form an array of suture knots, which are tightened, resulting in puncture edge apposition.
There remains a need for fast and straightforward mechanical and chemical systems and methods to close vascular puncture sites and to accelerate the patient""s return to ambulatory status without pain and prolonged immobilization.
The invention provides compositions, instruments, systems, and methods, which, in use, produce fast and effective closure to vascular puncture sites, and which allow a patient to return to ambulatory status quickly following a vascular access procedure.
One aspect of the invention a biocompatible and biodegradable barrier material, which is applied to seal a vascular puncture site. The barrier material comprises a compound, which is chemically cross-linked without use of an enzyme to form a non-liquid mechanical matrix.
In a preferred embodiment, the compound includes a protein comprising recombinant or natural serum albumin. In this embodiment, the compound also includes a polymer that comprises a poly(ethylene) glycol (PEG). Most preferably, the the PEG comprises a multi-armed polymer.
In a preferred embodiment, the barrier material, applied to seal a vascular puncture site, comprises a mixture of a first liquid component and a second liquid component, which are chemically cross-linked, without use of an enzyme, to form a non-liquid mechanical matrix.
This aspect of the invention also provides a kit comprising a first dispenser containing a first liquid component a second dispenser containing a second liquid component.
The kit includes instructions for handling the first and second dispensers according to a method comprising the steps of mixing the first and second liquid components to chemically cross-link the first and second components, without use of an enzyme, to form a non-liquid mechanical matrix, and applying the mechanical matrix to seal a vascular puncture site.
This aspect of the invention provides a chemically cross-linked barrier material that is not formed through the use of enzymes. Reliance upon enzymes as cross-linking agents can pose problems with regard to availability, cost, and possible viral transmission. The invention obviates these problems.
Another aspect of the invention provides a barrier material comprising a protein portion and polymer portion forming a cross-linked, hydrogel network. The barrier material is nontoxic, biodegradable, and possesses the mechanical properties necessary to seal arterial pressure.
In a preferred embodiment, the protein portion of the barrier material is a biocompatible, readily available, water soluble protein, such as a serum protein like albumin. The protein solution is preferably buffered to a pH in the range of 7.0 to 10.0.
In a preferred embodiment, the polymer portion of the barrier material is an electrophilic derivative of a hydrophilic polymer with a functionality of at least three. The preferred electrophilic group is an N-hydroxysuccinimide ester, due to its speed of reaction and low toxicity.
In a preferred embodiment, the polymer includes a region that controls degradation to impart biodegradation or non-biodegradation to the barrier material. The most preferred polymer for degradable barrier materials is poly(ethylene glycol) tetra-succinimidyl glutarate, however a number different polymers, electrophilic derivatives, and degradation control regions can be utilized.
Upon mixing, the polymer solution reacts with the protein solution, forming a cross-linked network in a prescribed amount of time. The rate of cross-linking can be controlled by the buffer in the protein solution. The mechanical properties of the barrier material can be controlled by the polymeric nature, structure, and concentration in the reactive mixture. The electrophilic derivative of the hydrophilic polymer not only reacts with the protein solution, but also reacts with the surrounding tissue in the site of application, creating an anchor for the material.
After the barrier material is formed, the degradation of the barrier material is controlled by the selection of the degradation control region. If degradation is desired, a degradation control region is selected that is able to be hydrolytically or enzymatically degraded in a physiological environment. The degrading molecules of the hydrogel barrier matrix are cleared through the kidneys and eliminated in the urine. If degradation is not desired, a degradation control region is selected that is stable in a physiological environment.
Another aspect of the invention provides systems and methods for creating and applying a biocompatible barrier in a tissue region. The systems and methods mix a protein solution and a polymer solution including a derivative of a hydrophilic polymer with a functionality of at least three. Upon mixing, the protein solution and the polymer solution cross-link to form a mechanical non-liquid matrix.
In a preferred embodiment, the systems and methods apply the barrier material to seal a vascular puncture site.